This project has evolved into the examination of the role of Fos in sensitization to cocaine. C-fos mRNA and the Fos protein have been shown to increase dramatically in the striatum following an acute injection of cocaine. With daily repeated injections, the Fos response returns to baseline levels. Paradoxically, this is at a time when the rats are behaviorally sensitized to cocaine; that is, following repeated adminis- tration more locomotion is induced in these rats with cocaine than in rats who receive cocaine for the first time. We have also found that while the induction of c-fos mRNA and the Fos protein are diminished with repeated exposure to cocaine, induction of another Fos-related protein (Fra) is not reduced. This may have important implications for switching of molecular responses with repeated cocaine and the manifested behavioral sensitization. In contrast to the differential changes in Fos and Fras in the striatum with cocaine sensitization, Fos increases in the hippocampus are seen only after cocaine-induced seizures, regardless of whether the cocaine is given acutely or repeatedly. Thus, different brain regions seem to participate in cocaine sensitization and seizures.